Abstract
This study investigated potential mechanisms by which age and IGF-I receptor (IGF-Ir) signaling in the neuroendocrine hypothalamus affect estradiol-positive feedback effects on GnRH neuronal activation and on kisspeptin and N-methyl-D-aspartate (NMDA)-induced LH release and on the abundance of NMDA receptor subunits Nr1 and Nr2b and Kiss1r transcript and protein in the hypothalamus of young and middle-aged female rats. We infused vehicle, IGF-I, or JB-1, a selective antagonist of IGF-Ir, into the third ventricle of ovariectomized female rats primed with estradiol or vehicle and injected with vehicle, kisspeptin (3 or 30 nmol/kg), or NMDA (15 or 30 mg/kg). Regardless of dose, NMDA and kisspeptin resulted in significantly more LH release, GnRH/c-Fos colabeling, and c-Fos immunoreative cells in young than in middle-aged females. Estradiol priming significantly increased Kiss1r, Nr1, and Nr2b receptor transcript and protein abundance in young but not middle-aged female hypothalamus. JB-1 attenuated kisspeptin and NMDA-induced LH release, numbers of GnRH/c-Fos and c-Fos cells, and Kiss1r, Nr1, and Nr2b transcript and protein abundance in young females to levels observed in middle-aged females. IGF-I significantly enhanced NMDA and kisspeptin-induced LH release in middle-aged females without increasing numbers of GnRH/c-Fos or c-Fos immunoreactive cells. IGF-I infusion in middle-aged females also increased Kiss1r, Nr1, and Nr2b protein and transcript to levels that were equivalent to young estradiol-primed females. These findings indicate that age-related changes in estradiol-regulated responsiveness to excitatory input from glutamate and kisspeptin reflect reduced IGF-Ir signaling.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Aging*
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Animals
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Female
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Gene Expression Regulation, Developmental / drug effects
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Hypothalamo-Hypophyseal System / growth & development
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Hypothalamo-Hypophyseal System / metabolism
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Hypothalamus / cytology
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Hypothalamus / drug effects
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Hypothalamus / growth & development
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Hypothalamus / metabolism
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Infusions, Intraventricular
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Insulin-Like Growth Factor I / administration & dosage
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Insulin-Like Growth Factor I / analogs & derivatives
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Insulin-Like Growth Factor I / antagonists & inhibitors
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Insulin-Like Growth Factor I / metabolism*
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Kisspeptins / metabolism*
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Luteinizing Hormone / metabolism*
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N-Methylaspartate / metabolism
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Nerve Tissue Proteins / agonists
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Neuroendocrine Cells / cytology
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Neuroendocrine Cells / drug effects
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Neuroendocrine Cells / metabolism
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Oligopeptides / administration & dosage
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Oligopeptides / pharmacology
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Rats
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Rats, Sprague-Dawley
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Receptor, IGF Type 1 / agonists*
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Receptor, IGF Type 1 / antagonists & inhibitors
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Receptor, IGF Type 1 / metabolism
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Receptors, G-Protein-Coupled / biosynthesis
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Receptors, G-Protein-Coupled / genetics
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Receptors, G-Protein-Coupled / metabolism
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Receptors, Kisspeptin-1
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Receptors, N-Methyl-D-Aspartate / agonists*
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Receptors, N-Methyl-D-Aspartate / genetics
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Receptors, N-Methyl-D-Aspartate / metabolism
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Signal Transduction / drug effects
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Synaptic Transmission* / drug effects
Substances
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Kiss1 protein, rat
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Kiss1r protein, rat
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Kisspeptins
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Nerve Tissue Proteins
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Oligopeptides
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Receptors, G-Protein-Coupled
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Receptors, Kisspeptin-1
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Receptors, N-Methyl-D-Aspartate
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insulin-like growth factor-1, rat
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H 1356
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N-Methylaspartate
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Insulin-Like Growth Factor I
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Luteinizing Hormone
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Receptor, IGF Type 1